Acetaminophen OD More Deadly if Taken in Stages

Action Points

Explain that staggered, excessive doses of acetaminophen over time and delayed presentation to the hospital after overdosing at a single time point were associated with poor outcomes among patients admitted to a specialized liver center.

Note that although those with a staggered acetaminophen overdose ingested a lower total amount of acetaminophen and had lower serum ALT levels at admission, they were more likely than other patients to be encephalopathic at admission and to require renal replacement therapy or mechanical ventilation.

Overdoses of acetaminophen were more likely to be fatal if patients consumed a series of high doses spread over the course of a day rather than downing, say, a bottle of pills at one time, outcomes among patients admitted to a specialized liver center showed.

Those who ingested more than 4,000 mg of acetaminophen in a single day spread out over more than one time point had a significantly higher mortality rate compared with those who overdosed at a single time point (37.3% versus 27.8%, P=0.025), according to Kenneth Simpson, MD, of the University of Edinburgh in Scotland, and colleagues.

Among those who overdosed at a single time point, presenting to the hospital more than 24 hours after ingestion was associated with a significantly greater likelihood of death or needing an orthotopic liver transplant (OR 2.25, 95% CI 1.23 to 4.12, P=0.009), the researchers reported online in the British Journal of Clinical Pharmacology.

"Patients presenting with these overdose patterns should be treated as high-risk for progression to acute liver failure, and should receive N-acetyl cysteine in their presenting hospital whilst awaiting serial alanine aminotransferase (ALT) and prothrombin time levels," they wrote.

Acetaminophen overdose is the leading cause of severe acute hepatotoxicity in Europe and North America, and Simpson and colleagues examined patterns of overdose and their association with outcomes among patients admitted to the Scottish Liver Transplantation Unit.

The cohort analysis included 663 patients admitted with acetaminophen-induced severe liver injury from November 1992 through October 2008. About one-quarter (24.3%) overdosed in a staggered fashion, defined as taking at least two excessive doses separated by more than eight hours and adding up to more than 4,000 milligrams in one day. The rest of the patients ingested that much at a single time point.

Most of the patients who had a staggered overdose (58.2%) said that pain relief was the reason they repeatedly took an excessive dose. Another 34.3% said it was a suicide attempt.

Although those with a staggered overdose ingested a lower total amount of acetaminophen and had lower serum ALT levels at admission, they were more likely than other patients to be encephalopathic at admission and to require renal replacement therapy or mechanical ventilation.

They had a higher mortality rate compared with those with an overdose at a single time point, although after accounting for demographics and clinical variables, the staggered pattern was not independently associated death or liver transplantation (OR 1.25, 95% CI 0.73 to 2.16, P=0.416).

Among patients with an overdose at a single time point, 44.9% presented to the hospital more than 24 hours after ingestion. That delay was associated with a poorer outcome.

Because that delay was associated with a poor outcome, "we therefore suggest that all patients with hepatotoxicity and delayed presentation following [acetaminophen] overdose receive N-acetyl cysteine treatment at their admitting hospital, irrespective of serum [acetaminophen] levels, and should be closely observed due to the high risk of progression to further organ injury," the researchers wrote.

They acknowledged some limitations of the study, including the reliance on patient recall for details about the overdose; possible misclassification of the overdose type; and the uncertain generalizability to an emergency department setting, where most of the cases of acetaminophen overdose are not as severe.

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